Identification of NOS2 as a protective locus against tuberculosis

Beatrice & Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, NY 10021, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/1997; 94(10):5243-8. DOI: 10.1073/pnas.94.10.5243
Source: PubMed


Mutagenesis of the host immune system has helped identify response pathways necessary to combat tuberculosis. Several such pathways may function as activators of a common protective gene: inducible nitric oxide synthase (NOS2). Here we provide direct evidence for this gene controlling primary Mycobacterium tuberculosis infection using mice homozygous for a disrupted NOS2 allele. NOS2(-/-) mice proved highly susceptible, resembling wild-type littermates immunosuppressed by high-dose glucocorticoids, and allowed Mycobacterium tuberculosis to replicate faster in the lungs than reported for other gene-deficient hosts. Susceptibility appeared to be independent of the only known naturally inherited antimicrobial locus, NRAMP1. Progression of chronic tuberculosis in wild-type mice was accelerated by specifically inhibiting NOS2 via administration of N6-(1-iminoethyl)-L-lysine. Together these findings identify NOS2 as a critical host gene for tuberculostasis.

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Available from: John S Mudgett, Dec 18, 2013
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    • "Further study found that EHEC possessing functional norV exhibited increased survival within macrophages compared to strains harboring the inactive norVs gene (Shimizu et al., 2012). Furthermore, murine infection studies have shown that deletion or inhibition of inducible nitric oxide synthase (iNOS), the enzyme responsible for NO • production in phagocytes (MacMicking et al., 1997), increases the bacterial load and mortality rate of infected hosts for a wide variety of pathogens (Richardson et al., 2011; MacMicking et al., 1995; Chan et al., 1995; Bang et al., 2006). These data suggest that sabotaging bacterial NO • defenses could constitute an effective anti-infective strategy for many pathogens. "
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    ABSTRACT: The importance of NO• to immunity is highlighted by the diversity of pathogens that require NO•-defensive systems to establish infections. Proteases have been identified to aid pathogens in surviving macrophage attack, inspiring us to investigate their role during NO• stress in Escherichia coli. We discovered that the elimination of ClpP largely impaired NO• detoxification by E. coli. Using a quantitative model of NO• stress, we employed an ensemble-guided approach to identify the underlying mechanism. Iterations of in silico analyses and corresponding experiments identified the defect to result from deficient transcript levels of hmp, which encodes NO• dioxygenase. Interestingly, the defect was not confined to hmp, as ΔclpP imparted widespread perturbations to the expression of NO•-responsive genes. This work identified a target for anti-infective therapies based on disabling NO• defenses, and demonstrated the utility of model-based approaches for exploring the complex, systems-level stress exerted by NO•. Copyright © 2015. Published by Elsevier Inc.
    Metabolic Engineering 06/2015; 31. DOI:10.1016/j.ymben.2015.06.005 · 6.77 Impact Factor
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    • "However, given the multifaceted role of nitric oxide in both the cytotoxicity and cytoprotection of pathogens, inhibiting nitric oxide production may also yield deleterious effects. For example, administration of the iNOS-2 inhibitor N 6 -(1-iminoethyl)-L-lysine caused accelerated progression of M. tuberculosis infection to chronic tuberculosis in murine lungs (MacMicking et al., 1997). "
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    ABSTRACT: The emergence and spread of drug-resistant pathogens and our inability to develop new antimicrobials to overcome resistance has inspired scientists to consider new targets for drug development. Cellular bioenergetics is an area showing promise for the development of new antimicrobials, particularly in the discovery of new anti-tuberculosis drugs where several new compounds have entered clinical trials. In this review, we have examined the bioenergetics of various bacterial pathogens, highlighting the versatility of electron donor and acceptor utilisation and the modularity of electron transport chain components in bacteria. In addition to re-examining classical concepts, we explore new literature that reveals the intricacies of pathogen energetics, for example, how Salmonella enterica and Campylobacter jejuni exploit host and microbiota to derive powerful electron donors and sinks; the strategies Mycobacterium tuberculosis and Pseudomonas aeruginosa use to persist in lung tissues; and the importance of sodium energetics and electron bifurcation in the chemiosmotic anaerobe Fusobacterium nucleatum. A combination of physiological, biochemical, and pharmacological data suggests that, in addition to the clinically-approved target F1Fo-ATP synthase, NADH dehydrogenase type II, succinate dehydrogenase, hydrogenase, cytochrome bd oxidase, and menaquinone biosynthesis pathways are particularly promising next-generation drug targets. The realisation of cellular energetics as a rich target space for the development of new antimicrobials will be dependent upon gaining increased understanding of the energetic processes utilised by pathogens in host environments and the ability to design bacterial-specific inhibitors of these processes.
    Advances in Microbial Physiology 11/2014; DOI:10.1016/bs.ampbs.2014.08.001 · 3.25 Impact Factor
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    • "An essential role for NO in the killing of Mtb by mononuclear phagocytes was demonstrated in a murine TB model [23], [24]. Furthermore iNOS deficient mice were highly susceptible to Mtb infection [11], [25], [26]. In contrast, the cytostatic and cytotoxic role of NO during Mtb infection in humans is debated, since early mycobacteriostatic activity of human macrophages was found to be independent of NO [27], [28]. "
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    ABSTRACT: Pulmonary tuberculosis (TB), caused by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb), is a major world health problem. The production of reactive nitrogen species (RNS) is a potent cytostatic and cytotoxic defense mechanism against intracellular pathogens. Nevertheless, the protective role of RNS during Mtb infection remains controversial. Here we use an anti-nitrotyrosine antibody as a readout to study nitration output by the zebrafish host during early mycobacterial pathogenesis. We found that recognition of Mycobacterium marinum, a close relative of Mtb, was sufficient to induce a nitrosative defense mechanism in a manner dependent on MyD88, the central adaptor protein in Toll like receptor (TLR) mediated pathogen recognition. However, this host response was attenuated by mycobacteria via a virulence mechanism independent of the well-characterized RD1 virulence locus. Our results indicate a mechanism of pathogenic mycobacteria to circumvent host defense in vivo. Shifting the balance of host-pathogen interactions in favor of the host by targeting this virulence mechanism may help to alleviate the problem of infection with Mtb strains that are resistant to multiple drug treatments.
    PLoS ONE 06/2014; 9(6):e100928. DOI:10.1371/journal.pone.0100928 · 3.23 Impact Factor
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